The goal of this proposal is to determine the function of an innate immunity regulator IL-1 receptor-associated kinase M (IRAK-M) during human rhinovirus (HRV) infection in the lung. HRVs are the most common viral infective agents in humans and the predominant cause of the common cold. Notably, HRVs are also the most common cause of exacerbations of several major respiratory diseases such as asthma. HRV primarily infects airway epithelium, but also affects lung macrophages. IRAK-M is critical to maintain tissue homeostasis, but excessive IRAK-M expression under diseased conditions likely predisposes patients to infections and disease exacerbations. We found increased IRAK-M in asthmatic airway epithelium and alveolar macrophages. Moreover, we discovered that Th2 cytokine IL-13 (a hallmark of allergic inflammation) increases IRAK-M. However, the role of IRAK-M in lung defense against HRV has not been explored. We found that baseline IRAK-M is pivotal in preventing excessive pro-inflammatory cytokine production upon HRV infection, but does not impair anti-viral responses. In contrast, IRAK-M up-regulation under a Th2 cytokine milieu enhances viral replication in part through autophagy. We hypothesize that IRAK-M up-regulation in allergic lungs (e.g., airway epithelial cells and alveolar macrophages) impairs anti-viral responses, predisposing the host to HRV infection and exacerbation of airway allergic inflammation. Three aims are proposed. Aim 1 will determine IRAK-M functions in normal lung defense against HRV infection. By using primary airway epithelial cells, macrophages, mouse bone marrow chimera models and conditional IRAK-M knockout mice, we will test if in normal lungs, IRAK-M prevents excessive inflammation during HRV infection, but does not impair the anti-viral mechanism. Aim 2 will define how IRAK-M up-regulation in a Th2 cytokine milieu promotes airway HRV infection. We propose that IRAK-M up-regulation by IL-13 inhibits type I and III interferon production, thus promoting autophagy and viral replication. We will perform mechanistic studies in airway epithelial cells and macrophages to determine if IRAK-M-mediated interferon inhibition promotes HRV replication via autophagy. Aim 3 will determine how HRV infection exaggerates airway allergic inflammation. We will test the hypothesis that IRAK-M/autophagy axis up-regulation in allergic lungs contributes to HRV-mediated exacerbation of airway allergic inflammation. We will define a critical role of IRAK-M/autophagy axis in HRV- mediated exaggeration of airway allergic inflammation in mice by targeting IRAK-M and autophagy. We then dissect the molecular mechanisms whereby IRAK-M/autophagy axis exaggerates airway allergic inflammation during HRV infection, which reciprocally up-regulates IRAK-M/autophagy axis. Defining the role of IRAK-M in HRV infection is likely to identify novel strategies for the prevention and treatment of acute asthma exacerbations, which afflict >18 million Americans, and cost >$28 billion/year.